Synthesis and Application of [ ¹⁸ F]Togni Reagent I: An Electrophilic ¹⁸ F‐Labeled Trifluoromethylating Reagent for Positron Emission Tomography Tracer Synthesis

The trifluoromethyl (CF 3 ) group is a ubiquitous motif in drug discovery campaigns due to its ability to markedly improve the ADME properties of small molecules while maintaining potency. The isotopologue labeling of CF 3 ‐bearing drugs with fluorine‐18 has gained attention for positron emission tomography (PET) imaging. However, their radiolabeling via conventional 18 F‐trifluoromethylation methods relies almost completely on nucleophilic and radical [ 18 F]CF 3 ‐reagents, whereas there remains no general means to incorporate a formal [ 18 F]CF 3 + into PET tracer candidates. Herein, we disclose the realization of a novel electrophilic 18 F‐labeled trifluoromethylating reagent based on the family of 10‐λ‐3 hypervalent iodines: [ 18 F]Togni reagent I. The method uses nucleophilic ligand substitution at iodine by the [ 18 F]Ruppert–Prakash reagent, providing [ 18 F]Togni reagent I in a radiochemical yield of 4.3 ± 0.8% and a molar activity of 15 ± 9.6 GBq/μmol. Initial studies on the utility of this reagent demonstrate the direct, late‐stage formation of C(sp 3 )−[ 18 F]CF 3 bonds via metallaphotoredox‐mediated conversion of naturally abundant carboxylic acids. Hence, this work illustrates the potential of the novel electrophilic [ 18 F]CF 3 ‐reagent as a complementary approach leading to valuable 18 F‐trifluoromethylated architectures in PET tracer development.